The fundamental premise underlying this proposal is that the normal program of differentiation in the adult mammalian myocardium changes in response to age and that these changes contribute to age-related differences in susceptibility to hypoxia and ischemia. Our major hypotheses are that the integration of the metabolic pathways for ATP synthesis and utilization changes during aging and, as a consequence, aged myocardium is more susceptible to acute hypoxic and ischemic injury. Corollary hypotheses are (1) that these changes are similar to those observed in chronic hypoxia and many forms of hypertrophy, (23) that decreased energy reserve (the CK system) contributes to increased susceptibility and (3) that changes in glycolytic capacity of the aged myocardium contribute to differences in pHi regulation during hypoxia.